The research described in this application consists of extension of earlier ones that we presented in our initial application. They consist of studies of the influence of many different factors on insulin and glucagon secretion. Many of the investigations are conducted in vivo and many others by in vitro. Isolated islets and cultured islet cells are used. In addition to investigating the influence of many different hormones we are studying the effect of changes in cyclic nucleotide levels in the islets. We are investigating the effect of insulin on cyclic nucleotide metabolism in fibroblasts, skeletal muscle cells, smooth muscle cells, liver, heart, and adipose tissue cells. We have underway investigations to extract proinsulin, insulin and intermediary compounds from the plasma of normal and diabetics, and we will attempt to determine whether or not abnormal insulin products are secreted in diabetics. We are also continuing to study the influence of a number of physiological changes, such as the effect of a decrease in blood sugar on plasma epinephrine and norepinephrine. We are investigating the effects of the following compounds on gastrin secretion, using an isolated segment of gastric mucosa: insulin, glucagon, prostaglandin, somatostatin, growth hormone, parathyroid hormone, acetylcholine, epinephrine, and other compounds.